Cardiovascular regulation during exercise is subject to major input from the neuromuscular system. However, in comparison with other experimental models, there has been limited study of human muscular and neuromuscular disease states. The proposed study examines the roles of central command (cortical activation of the medullary cardiovascular control centers as part of the motor outflow to skeletal muscle), local metabolic state (substances produced by working muscle which stimulate the nerve endings of afferent fibers as part of peripheral reflex cardiovascular control), active muscle mass (estimated by total body oxygen uptake) and relative load (percentage of muscle group specific maximum) in circulatory control during exercise in patients with muscular and neuromuscular diseases. The role of local metabolic state will be studied in detail in patients with well characterized skeletal muscle myopathies. These experiments will be carried out firstly, by relating the oxygen uptake, cardiac output (C2H2 rebreathing), heart rate, and blood pressure responses to a variety of exercise modes (i.e., static vs. dynamic, small vs. large muscle, etc.) to histochemcial and in vitro biochemical properties of muscle tissue; secondly, by determining the cardiovascular responses to exercise after modification of the type of metabolic fuel combusted; and thirdly, by studies of working muscle oxygen uptake, blood flow (dye dilution), and metabolite release and by biochemical analysis of muscle biopsy material obtained in connection with exercise. Treated and untreated patients with myasthenia gravis will be studied to evaluate the interaction between central command and other determinants of the exercise response. The results of this project will provide unique information regarding the mechanisms of human circulatory control during exercise and models upon which future investigations may be based.